Tau is essential to beta -amyloid-induced neurotoxicity - PubMed (original) (raw)

Tau is essential to beta -amyloid-induced neurotoxicity

Mark Rapoport et al. Proc Natl Acad Sci U S A. 2002.

Abstract

Senile plaques and neurofibrillary tangles, the two hallmark lesions of Alzheimer's disease, are the results of the pathological deposition of proteins normally present throughout the brain. Senile plaques are extracellular deposits of fibrillar beta-amyloid peptide (Abeta); neurofibrillary tangles represent intracellular bundles of self-assembled hyperphosphorylated tau proteins. Although these two lesions are often present in the same brain areas, a mechanistic link between them has yet to be established. In the present study, we analyzed whether tau plays a key role in fibrillar Abeta-induced neurite degeneration in central neurons. Cultured hippocampal neurons obtained from wild-type, tau knockout, and human tau transgenic mice were treated with fibrillar Abeta. Morphological analysis indicated that neurons expressing either mouse or human tau proteins degenerated in the presence of Abeta. On the other hand, tau-depleted neurons showed no signs of degeneration in the presence of Abeta. These results provide direct evidence supporting a key role for tau in the mechanisms leading to Abeta-induced neurodegeneration in the central nervous system. In addition, the analysis of the composition of the cytoskeleton of tau-depleted neurons suggested that the formation of more dynamic microtubules might confer resistance to Abeta-mediated neurodegeneration.

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Figures

Figure 1

Figure 1

Fibrillar Aβ induced neurite degeneration in mature hippocampal neurons. Hippocampal neurons obtained from wild-type E16 embryos were kept in culture for 4 weeks (A and B) and then incubated in the presence of fibrillar Aβ for 4 days (C and D). Cells were fixed and double stained with tubulin (polyclonal antitubulin, Sigma) (A and C) and tau (clone tau-5) (B and D) antibodies. Note the massive neurite degeneration induced by fibrillar Aβ (C and D). (Bar = 20 μm.)

Figure 2

Figure 2

Tau-depleted hippocampal neurons did not degenerate in the presence of fibrillar Aβ. Hippocampal neurons obtained from tau knockout E16 embryos were kept in culture for 4 weeks (A and B) and then incubated in the presence of fibrillar Aβ for 4 days (C and D). Cells were fixed and double stained with tubulin (polyclonal antitubulin, Sigma) (A and C) and tau (clone tau-5) (B and D) antibodies. Most of the processes extended by tau knockout neurons showed normal morphological characteristic in the presence of fibrillar Aβ (C). (Bar = 20 μm.)

Figure 3

Figure 3

Cultured hippocampal neurons expressing human tau degenerated in the presence of fibrillar Aβ. Hippocampal neurons obtained from human tau transgenic mice were kept in culture for 4 weeks and then incubated in the presence (C and D) or absence (A and B) of fibrillar Aβ for 4 days. Cells were fixed and double stained with tubulin (polyclonal antitubulin, Sigma) (A and C) and tau (clone tau-5) (B and D) antibodies. (Bar = 20 μm.)

Figure 4

Figure 4

(A) Western blot analysis of the content of microtubular proteins in wild-type (wt), human tau transgenic (htau transg), and knockout (KO) tau hippocampal neurons kept in culture for 4 weeks and incubated in the presence or absence of fibrillar Aβ for 4 days. Equal amounts of total protein (40 μg) were loaded in each lane. (B) Western blot analysis of the content of α-tubulin and detyrosinated tubulin in cytoskeletal fractions prepared from wild-type (wt), human tau transgenic (htau transg), and knockout (KO) tau hippocampal neurons kept in culture for 4 weeks and incubated in the presence or absence of nocodazole or Taxol. Nocodazole-resistant fractions were normalized using the content of α-tubulin as internal controls.

Figure 5

Figure 5

Fibrillar Aβ induced neurite degeneration in Taxol-treated tau-depleted hippocampal neurons. Wild-type (A and B), tau knockout (C and D), and human tau transgenic (E and F) hippocampal neurons kept in culture for 4 weeks were pretreated with Taxol for 6 h and then cultured for 24 h in the presence (B, D, and F) or absence (A, C, and E) of fibrillar Aβ. Cells were then fixed and stained by using a tubulin antibody (clone DMIA, SIGMA). Severe neurodegeneration was detected in Taxol-treated tau knockout hippocampal neurons exposed to fibrillar Aβ (D) as well as in neurons expressing either murine (B) or human (F) tau isoforms. (Bar = 20 μm.)

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